We uncovered a potential mechanism for rheumatoid arthritis (RA) by performing whole exome sequencing (WES) in a family with a rare autosomal dominant form of RA characterized by interstitial lung disease (ILD). We found a single, rare, non-synonymous variant on chromosome 10 in the Surfactant Protein A2 (SFTPA2) gene (c.G532A:p.V178M) present only in diseased subjects. This result was unexpected given that the dominant phenotype in our patients is RA. Published evidence suggests that the variant we identified causes an increase in ER stress, though to our knowledge there are no reported molecular links between mutations in the lung and the development of RA. Interestingly, increasing evidence points to a central role of the lung in a subset of patients with RA. Observational studies show that cigarette smokers that express the HLA-DRB1 shared epitope (SE) alleles have a significantly elevated risk for developing RA. Cigarette smokers have more citrullinated proteins in the lung compared to non-smokers and one possible reason for this is that undefined bronchiolar stress from cigarette smokes promotes citrullination of lung proteins. In relation to RA, antibodies to citrullinated proteins have been found in a significant portion of patients with RA. We propose that the SFPTA2 mutation identified in this family leads to increased ER stress in the lung, which then promotes lung protein citrullination, and that via T cell-related mechanisms, this results in a phenotype of RA and possibly RA-ILD. Using patient cell lines and molecular tools developed in the lab, we are defining the functional consequences of the mutation we identified on ER stress as well as citrullination of proteins. Through experiments in humanized mice, we are studying the role of the lung epithelium in the initiation of RA.